Microneedle array module and method of fabricating the same

ABSTRACT

A microneedle array module is disclosed comprising a multiplicity of microneedles affixed to and protruding outwardly from a front surface of a substrate to form the array, each microneedle of the array having a hollow section which extends through its center to an opening in the tip thereof. A method of fabricating the microneedle array module is also disclosed comprising the steps of: providing etch resistant mask layers to one and another opposite surfaces of a substrate to predetermined thicknesses; patterning the etch resistant mask layer of the one surface for outer dimensions of the microneedles of the array; patterning the etch resistant mask layer of the other surface for inner dimensions of the microneedles of the array; etching unmasked portions of the substrate from one and the other surfaces to first and second predetermined depths, respectively; and removing the mask layers from the one and the other surfaces. One embodiment of the method includes the steps of: providing an etch resistant mask layer to the other surface of the substrate to a predetermined thickness; patterning the etch resistant mask layer of the other surface to define a reservoir region in the substrate; and etching away the unmasked reservoir region of the substrate to form a reservoir well in the other surface of the substrate. A layer of material may be provided to the other surface to enclose the reservoir well and a passageway is provided through the layer to the well region.

This application is a continuation of U.S. patent application Ser. No.10/162,848, filed on Jun. 5, 2002, now U.S. Pat. No. 6,790,372, which isa Divisional of U.S. patent application Ser. No. 09/643,103 filed Aug.21, 2000 (now abandoned).

BACKGROUND OF THE INVENTION

The present invention is related to microelectromechanical systems(MEMS) and the fabrication thereof, in general, and more specifically,to a microneedle array module and its fabrication.

Targeted drug delivery or the application of a high concentration of oneor more drugs to a specific target area within the body has become ofparamount importance to the fight against tumors, restentosis andsimilar life threatening medical conditions. Generally, these targetareas are reachable through the walls of the blood vessels of the body.Present systems use a catheter with an imaging device to locate thetarget area. Once located, a specific drug or drugs are delivered to thetargeted vessel wall area. But, this process has posed serious problems.

One approach provides a drug inside a perforated balloon at the end ofthe catheter. When the balloon reaches the target area, it is inflatedcausing the drug to be released through the perforations of the balloonlocally around the targeted walls of the vessel. This perfusion of thedrug at the surface of the vessel walls relies heavily on the drug beingabsorbed quickly and efficiently by the vessel walls at the target area.However, in some cases the drug may not be absorbed by the vessel wallsvery effectively. In these cases, the drug may be caused to movedownstream with the blood stream which may cause adverse medical effectsto portions of the body not intended to receive the drugs, especially atsuch high concentrations. The drugs may also be diluted in this deliveryprocess and lose their effectiveness. In any event, these relativelyexpensive drugs may not be achieving their intended purpose.

Some recent drug delivery systems, like those proposed in the U.S. Pat.Nos. 5,112,305; 5,242,397; 5,681,281; 5,713,863 and 5,746,716, forexample, provide for a studded balloon catheter. The balloon or portionsthereof contain the drug or drugs to be delivered to the target area.When the balloon reaches the target area, it is inflated causing thestuds to press against the vessel walls. The drug is then forced fromthe balloon through the studs into the surface of the vessel walls.However, the stud protrusions of the balloon are not needles and thus,are not very efficient at puncturing the vessel walls, especially atdepths adequate for injecting the specific drug.

What is needed for effective drug delivery is an array of microneedlesof sufficient length which may be deployed to the target site within thebody and adequately penetrate the vessel walls thereat to permit thedrug to effectively act on the target area at the high concentrationsintended. Such an array structure may also be used transdermally fordrug delivery as well.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, a microneedlearray module comprises a multiplicity of microneedles affixed to andprotruding outwardly from a front surface of a substrate to form thearray, each microneedle of the array having a hollow section whichextends through its center to an opening in the tip thereof. Thesubstrate includes an array of holes which align with the hollowsections of the microneedles and extend through the substrate to a backsurface thereof, whereby a liquid applied to the back surface of thesubstrate may be forced through the holes in the substrate and outthrough the tips of the microneedle array thereof. In one embodiment,the substrate includes a reservoir well in the back surface thereof. Thewell extends over the array of holes in the back surface and may becovered by a layer of material which is affixed to the back surfaceperipheral the well, the layer including an interconnecting passagewayto the well.

In accordance with another aspect of the present invention, a method offabricating a microneedle array module comprises the steps of: providingetch resistant mask layers to one and another opposite surfaces of asubstrate to predetermined thicknesses; patterning the etch resistantmask layer of the one surface for outer dimensions of the microneedlesof the array; patterning the etch resistant mask layer of the othersurface for inner dimensions of the microneedles of the array; etchingunmasked portions of the substrate from one and the other surfaces tofirst and second predetermined depths, respectively; and removing themask layers from the one and the other surfaces. One embodiment of themethod includes the steps of: providing an etch resistant mask layer tothe other surface of the substrate to a predetermined thickness;patterning the etch resistant mask layer of the other surface to definea reservoir region in the substrate; and etching away the unmaskedreservoir region of the substrate to form a reservoir well in the othersurface of the substrate. A layer of material may be provided to theother surface to enclose the reservoir well and a passageway is providedthrough said layer to the well region.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1H are cross-sectional illustrations exemplifying a method offabricating a microneedle array module in accordance with the presentinvention.

FIGS. 2A-2G are cross-sectional illustrations exemplifying an alternatemethod of fabricating a microneedle array module.

FIGS. 3A and 3B depict two three-dimensional perspectives of anexemplary embodiment of a microneedle array module in accordance withthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1A-1H and FIGS. 2A-2G are illustrations of two exemplary methods offabricating a microneedle array module. FIGS. 1G and 2F depictcross-sectional views of alternative embodiments of microneedle arraystructures having microneedles cylindrical in shape and conical inshape, respectively. The structures of FIGS. 1G and 2F result from theirrespective fabrication methods. FIGS. 3A and 3B depict twothree-dimensional perspectives of the exemplary resulting microneedlearray module shown in the cross-sectional view of FIG. 2F. FIGS. 1H and2G provide cross sectional views of further embodiments of the arraystructure in which a reservoir well thereof is covered as will becomebetter understood from the description found herein below.

In FIG. 1A is shown a substrate 10 having a front surface 12 and backsurface 14. The substrate 10 may be comprised of Silicon or a glassmaterial, or a form of SiO₂, like pyrex, for example, and be on theorder of four hundred micrometers (400 μm) thick, for example. In thepresent embodiment, the substrate 10 is part of a double side polished(100) Silicon wafer that may be on the order of one hundred millimeters(100 mm) in diameter. Next, in the step of FIG. 1B, an etch resistantmask layer 16 is provided to both of the front and back surfaces of thesubstrate 10. In the present embodiment, the wafer is thermally oxidizedto grow a one thousand Angstrom (1000 Å) thick film of SiO₂ on bothsurfaces 12 and 14. The front and back surfaces may also be oxidized bychemically depositing an oxide thereon. In any event, it is furtherunderstood that other forms of etch resistant masks may be used such asproviding a layer of Silicon Nitride or of a photoresist to thesurfaces, for example, without deviating from the principles of thepresent invention.

Also, in the step of FIG. 1B, the etch resistant mask of the backsurface 14 is patterned using a conventional photolithography process,for example, to define a reservoir region 20 in the substrate 10 and thereservoir pattern of the SiO₂ film is etched using buffered hydrofluoricacid (BHF) or fluorocarbon (CHF₃)-based reactive ion etching (RIE), forexample, to realize an unmasked reservoir region. Next, the unmaskedreservoir region 20 of substrate 10 is etched to a depth ofapproximately 10-20 μm using a Potassium Hydroxide (KOH) or SiliconFluoride (SF₆)-based RIE, for example, to form a reservoir well 22 inthe back surface 14. Subsequently, the etch resistant mask on the backsurface 14 is removed using a BHF etch.

Another etch resistant mask layer 16 is provided over the back surface14 including the well region 22 to an approximate thickness of 1.5 μm,for example, using a thermal oxidation process or other process in asimilar manner as described above and is patterned using a conventionalthick photoresist photolithography and a BHF etch or fluorocarbon-basedRIE process to define the inner dimensions or openings of themicroneedles of the array, which may be on the order of 15-20 μm, forexample, as shown in FIG. 1C. In the step of FIG. 1D, the unmaskedportions 24 of the back surface 14 including the well or reservoirregion 22 are etched to a predetermined depth, say on the order of 350μm, for example. In the present embodiment, the substrate is etchedanisotropically using a deep reactive ion beam etching (RIE) process,preferably using a Silicon Fluoride (SF₆) based ion beam. This etchingleaves only thin layers 26 of the substrate relative to the thickness ofthe substrate. In the present embodiment, these thin layers 26 may be onthe order of 40-50 μm, for example.

In the step of FIG. 1E, the etch resistant layer 16 of the front surface12 is patterned, preferably using a conventional thick photoresistphotolithography process and fluorocarbon-based RIE, to define the outerdimensions of the microneedles of the array, which may be on the orderof 25-30 μm, for example. The unmasked portions 28 of the substrate 10are similarly anisotropically etched using the deep RIE process toanother predetermined depth leaving substantial layers 30 of substrate10, say on the order of 80-90 μm, for example, under the masked layerpatterns 16 at the back surface 14 as shown in FIG. 1F. Thereafter, theetch resistant masks 16 are removed from the front and back surfaces 12and 14, respectively, preferably using a buffered hydrofluoric acidwash. Next, the thin layers of unetched substrate 26 are removed,preferably by anisotropic etching, from the front surface 12 using thedeep without any etch mask to provide openings 32 for the tips of themicroneedles of the array as shown in FIG. 1G. Finally, as shown in FIG.1H, a layer of material 34, preferably a Pyrex wafer, is provided overthe back surface 14 about the periphery of the well region 20 to enclosethe reservoir. However, it is understood that this layer of material 34is not limited to pyrex, but rather may include at least one materialselected from the group of silicon, ceramic, plastic and some form ofSiO₂, for example. A passageway 36 is provided through said layer 34 tothe well region 20. In the present embodiment, the pyrex layer 34 isanodically bonded to the surface 14 and the passageways 36 are createdby ultrasonic drilling through the pyrex layer 34. It is furtherunderstood that other standard methodologies to attaching the enclosingwafer and creating passageways therein may also be utilized withoutdeviating from the principles of the present invention.

The resulting fabricated microneedles of the array protruding from theremaining layer 30 of the substrate 10 are cylindrical in shape andsubstantially the same in dimension, having approximately 300 μm inheight, for example. However, it is understood that the foregoingdescribed fabrication process may produce microneedles having heightdimensions that are greater than the dimension of the remainingthickness 30 of the substrate material. In addition, the fabricationprocess described above may be applied to starting substrates ofdifferent thicknesses to produce protruding dimensions of themicroneedles that may range from 50-2000 μm, for example. Accordingly,the resulting microneedle array module comprises: a substrate havingfront and back surfaces; and a multiplicity of microneedles thatprotrude outwardly from the front surface to form the array, eachmicroneedle including a hollow section which extends through its centerto an opening in the tip thereof. The substrate includes an array ofholes which align with the hollow sections of the microneedles andextend to the back surface as shown in FIG. 1G, whereby a liquid appliedto the back surface may be forced through the holes in the substrate andout through the tips of the microneedles of the array. In the presentembodiment, the microneedles are fabricated from the substrate and forman integral part thereof. Also, a reservoir well 22 is provided in theback surface and extends over the array of holes in the substrate. Alayer of material 34 covering the well 22 is affixed to the back surfaceperipheral the well region 20 and includes an interconnecting passageway36 to the well through which liquid may flow.

While the fabrication method described in connection with FIGS. 1A-1Hprovide microneedles of cylindrical shape. It is understood that suchmicroneedles may also be fabricated in other shapes, like for example ina conical shape. The method of FIGS. 2A-2G illustrate the steps of amethod which produce a module having an array of conically shapedneedles. In FIGS. 2A-2G, reference numerals for the steps will remainthe same as used to describe the method of FIGS. 1A-1H. Referring toFIGS. 2A-2G, the steps of this alternative process remain the same asthat described herein above down through FIG. 2D wherein the etchresistant masks 16 of the front and back surfaces are patterned todefine the inner and outer dimensions, respectively, of the microneedlesof the array. In FIG. 2D, the unmasked portions 24 of the substrate 10are etched anisotropically using the same or similar deep RIE process toa depth which creates openings 40 under the masks 16 at the frontsurface 12. These openings 40 form the tips of the microneedles of thearray.

In FIG. 2E, the unmasked portions 42 of the front surface are etchedanisotropically using the same or similar deep RIE process controlled tocontour the sides of the etched wells 46 in the substrate 10 to form theconical shape of the microneedles. In the present embodiment, processparameters, including gas pressures and voltages, for example, in thedeep RIE process are adjusted to control the contour of the etchedsidewalls of the microneedles. The paper entitled “Dry Silicon EtchingFor MEMS” by J Bhardwaj et al., which was presented at the Symposium onMicrostructures and Microfabricated Systems at the annual meeting of theElectrochemical Society, Montreal Quebec, Canada, May 4-9, 1997, whichis incorporated by reference herein for providing the details of a deepRIE process suitable for use in the fabrication methods. A similarremaining substrate layer 30 is left from the etching process under themasked regions 16 at the back surface 14. Thereafter, the etch resistantpatterned masks 16 are removed from the front and back surfaces 12 and14, respectively, preferably using a BHF etch. Note that the resultingstructure depicted in FIG. 2F provides for openings 40 at the tips ofthe microneedles without further fabrication. In FIG. 2G, the layer 34is bonded to the back surface 14 to enclose the reservoir region 20, ifappropriate, and passageway 36 provided in the same or similar manner asthat described in connection with FIG. 1H herein above.

Two three-dimensional views of one embodiment of a microneedle arraymodule is shown in FIGS. 3A and 3B. This exemplary module has outsidedimensions of approximately one millimeter (1 mm) by one-half amillimeter (0.5 mm) and includes more than ten rows of microneedles witheach row including approximately seven microneedles, for example, torender an array of approximately one-hundred microneedles. An array ofholes through the substrate and aligned with the microneedles are shownin the reservoir region. Thus, liquid applied to the reservoir regionmay be forced through the holes and out of the tips of the microneedlesof the array.

While the present invention has been described herein above inconnection with one or more embodiments, it is understood that theseembodiments are used merely by way of example. Accordingly, the presentinvention should not be limited to any such embodiments, but ratherconstrued in breadth and broad scope in accordance with the appendedclaims.

1. A method of fabricating a microneedle array module comprising thesteps of: providing etch resistant mask layers to a first surface of asubstrate to predetermined thicknesses; patterning the etch resistantmask layer of the first surface for outer dimensions of the microneedlesof said array; etching unmasked portions of said substrate from thefirst surface to a first predetermined depth; anisotropically etchingunderneath masked portions of the substrate from a second surface of thesubstrate to a second predetermined depth; and removing the mask layersfrom the the first surface.
 2. The method of claim 1 wherein the step ofproviding includes oxidizing the surfaces of the substrate topredetermined thicknesses.
 3. The method of claim 2 wherein the step ofoxidizing includes the step of thermally oxidizing the surfaces.
 4. Themethod of claim 2 wherein the step of oxidizing includes chemicallydepositing an oxide on the surfaces.
 5. The method of claim 1 whereinthe step of providing includes the step of providing a mask layer ofsilicon nitride to the surfaces of the substrate.
 6. The method of claim1 wherein the step of providing includes the step of providing a masklayer of photoresist to the surfaces of the substrate.
 7. The method ofclaim 1 wherein the unmasked portions of the substrate are etchedanisotropically.
 8. The method of claim 7 wherein the unmasked portionsof the substrate are anisotropically etched using a deep reactive ionbeam etching (RIE) process.
 9. The method of claim 8 wherein the deepRIE process uses a SF₆ based ion beam.
 10. The method of claim 1 whereineach step of patterning includes the steps of patterning the etchresistant mask layer using a photolithography process.
 11. The method ofclaim 1 wherein the mask layers are removed away using a bufferedhydrofluoric acid.
 12. The method of claim 1 wherein the mask layers areremoved away using a reactive ion etching (RIE) process.
 13. The methodof claim 12 wherein the mask layers are removed away using afluorocarbon-based RIE.
 14. The method of claim 1 wherein the secondpredetermined etching depths are greater than the first predeterminedetching depths.
 15. The method of claim 14 wherein the second etchingdepths leaving only thin layers of substrate at the one surface relativeto the thickness of the substrate; and wherein the thin layers ofunetched substrate portions are etched from the one surface to provideopenings for microneedle tips of the array.
 16. The method of claim 14wherein the second etching depths creating openings in the one surfacefor the microneedle tips of the array.
 17. The method of claim 1including the steps of: providing an etch resistant mask layer to theother surface of the substrate to a predetermined thickness; patterningthe etch resistant mask layer of the other surface to define a reservoirregion in the substrate; and etching away the unmasked reservoir regionof the substrate to form a reservoir well in the other surface of thesubstrate.
 18. The method of claim 17 including the steps of: providinga layer of material to the other surface to enclose the reservoir well;and providing a passageway through said layer to the well region. 19.The method of claim 18 including the reservoir well is enclosed by abonding a layer of material to the other surface.
 20. The method ofclaim 19 wherein the material of the layer bonded to the other surfaceis selected from the group consisting of a form of SiO₂, silicon,ceramic, and plastic.